Aminoalkyl 3beta, 17beta-dihydroxyandrost-5-en-17alpha-ylpropiolates and 3-oxo-5-enes corresponding



United States Patent 3,183,227 AMINOALKYL 3fi,17fl-DIHYDROXYANDROST-5- EN-17oc-YLPROPIOLATES AND 3-0X0-5-ENES CORRESPONDING Robert W. Hamilton, Wilmette, and Kurt J. Rorig, Glenview, 11]., assignors to G. D. Searle & Co., Chicago, Ill., a corporation of Delaware e No Drawing. Filed Sept. 17, 1963, Ser. No. 309,460 9 Claims. (Cl. 260-2395) This invention relates to aminoalkyl 35,17B-dihydroxyandrost-S-en-17a-ylpropiolates, 3-oxo-5-enes corresponding, and processes for the manufacture thereof. More particularly, this invention providesnew, useful, and unobvious chemical compounds of the formula wherein n represents a positive integer less than 8.

Am in thegeneric formula for compounds of this invention subsumes both the primary amino radical, --NH and secondary and most advantageously tertiary amino radicals resulting from the substitution of 1 or 2 alkyl radicals, respectively, for hydrogen therein-especially lower alkyl radicals, such as methyl, ethyl, propyl, ism propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, isohexyl, heptyl, and like monovalent, saturated, acyclic, straightor branched-chain, hydrocarbon groupings having the formula wherein n represents, as before, a positive integer less than 8. The alkyl groupings present when Am designates a tertiary amino radical may either be discrete, thus or they may be joined together directly or through oxygen or a second nitrogen atom 'to. compose cyclic amino radicals. Representative of cyclic amino radicals contemplated by Am are pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, trimethylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, methylethylpiperidino, morpholino, piperazino, methylpi-perazino, ethylpiperazino and like nionovalent, 5- and 6-membered heterocyclic groupings. The terminal ino in the radical names set 7 O forth denotes attachment of the radicals thus characterized via nitrogen.

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Equivalent to the foregoing basic esters of this invention for the purposes here disclosed are non-toxic acid addition salts thereof, the compositions of which may be symbolized by r 5 M CH wherein X, Alk, Am, and the dotted line retain the meanings previously assigned; T represents 1 equivalent of an anion-for example, chloride, bromide, iodide, nitrate, phosphate, sulfate, sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate, toluenesulfonate, acetate, lactate, succinate, malate, maleate, tartrate, citrate, gluconate, ascorbate, benzoate, cinnamate, or the likewhich, in combination with the'cationic portion of a salt aforesaid, is neither pharmacologically nor otherwise undesirable in pharmacleuticsal dosage; and x represents a positive integer less t an The compounds to which this invention relates are useful because of their valuable pharmacological properties. Thus, for example, they are anti-hypertensive and, as

evidenced by their capacity to reduce the heat, swelling, and rubor characteristic of the inflammatory response to tissue insult, anti-inflammatory.

Manufacture of the basic esters. hereof proceeds by heating an appropriate acid of the formula CEC-COOH 3 5 and aminoalkyl halide of the formula admixture thereof with 1 or 2 equivalents of any of various inorganic and strong organic acids, the anionic portion of which conforms to T as hereinbefore assigned.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their preparation. However, the

0 invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the, art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees centigrade and relative amounts of materials in parts by Weight, except as otherwise noted.

Example 1 3 parts of 35,17fi-dihydroxyandrost-S-en-l7a-ylpropiolic acid (preparable by the procedure of Example 1A in US. 2,705,712), 34 parts of dirnethylaminoethyl chloride, and 4000 parts of absolute 2-propanol is heated at the boiling point under reflux in an atmosphere of nitrogen for 3 hours, whereupon solvent is removed by vacuum distillation. The residue is taken up in 900 parts of 90% ethanol and the resultant solution precipitated with 1600 parts of anhydrous ether. The precipitate, filtered off and twice reprecipitated from 90% ethanol with anhydrous ether, affords 2-dimethylaminoethyl 3/3,l7fi-dihydroxyandrost-5- en-l7a-ylpropiolate hydrochloride melting at approximately 255 with gas evolution. The product has the formula CEC O O CH2CH2N (CH3); E3 OH B. 2 dimethylaminoethyl 313,17B-dihydr0xyandr0st-5- ell-17 xylpr0pi0late.Approximately 10 parts of Z-dimethylaminoethyl 3,9,17,B-dihydroxyandrost-S-en-17a-ylpropiolate hydrochloride is partitioned between aqueous potassium carbonate and chloroform. The chloroform phase is separated, washed with water, and stripped of solvent by vacuum distillation. The residue is Z-dimethylaminoethyl 318,17fl-dihydroxyandrost-5-en-l7u-ylpropiolate.

Example 2 Z-diethylaminoethyl 313,1 7(3-dihydroxyandrost-S-en-I 7aylpropiolate hydrochloride.A mixture of 300 parts of 313, 17,8-dihydroxyandrost-S-en-17a-ylpropiolic acid, 113 parts of diethylaminoethyl chloride, and 4000 parts of absolute 2-propanol is heated at the boiling point under reflux for 3 hours. The solvent is thereupon distilled off under reduced pressure and the residue taken up in 8000 parts of absolute ethanol. To the ethanol solution is added just sufi'icient 2-propanolic hydrogen chloride to insure acidity, followed by 16,000 parts of anhydrous ether. The 2-diethylaminoethyl 3B,17fi-dihydroxyandrost-S-en-17a-ylpropiolate hydrochloride which crystallizes out melts at 204- 209 with gas evolution. The product has the formula CECCOO CH C H1N(C2H6)2 Example 3 Z-diethylaminoethyl 17/3-hydr0xy 3 oxoandrostl-en- 17a-ylpropi0late hydr0chl0ride.A mixture of parts of 17fi-hydroxy-3-0xoandrost-4-en-l7a-ylpropiolic acid (preparable from the product of Example 1A in US. 2,705,712 by Oppenauer oxidation as taught at lines 44-51 of column 4 therein), 13 parts of diethylaminoethyl chloride, and 450 parts of Z-butanol is heated at the boiling point under reflux for 16 hours, whereupon solvent is stripped by vacuum distillation. The residue is taken up in 200 parts of absolute ethanol, and the ethanol solution is diluted with 200 parts of anhydrous ether. A small amount of precipitate is filtered off and discarded. To the filtrate is added 400 parts of anhydrous ether. The resultant precipitate is Z-diethylaminoethyl 17,8-hydroxy-3-oxoandrost- 4-en-l7a-ylpropiolate hydrochloride which, filtered off and dried in air, melts at approximately with gas evolution. The product has the formula fil .HCl

Example 4 3 dimethylaminopropyl 35,1719 dihydroxyandrost-5- en-17ot-ylpropi0late hydr0chl0ride.A mixture of 30 parts of 35,-17/3-dihydroxyandrost 5 en-17u-ylpropiolic acid, 11 parts of 3-dimethylaminopropyl chloride, and 2000 parts of absolute 2-propanol is heated at the boiling point under reflux for 16 hours. Just sufiicient solvent is removed by vacuum distillation to induce the formation of a precipitate. The precipitate is filtered oil and discarded. The filtrate is stripped of solvent by vacuum distillation and the residue taken up in 800 parts of absolute ethanol. To the ethanol solution is added 800 parts of anhydrous ether. The precipitate which forms is filtered off and recrystallized from absolute ethanol and anhydrous ether to give 3-dimethylaminopropyl 35,17fidihydroxyandrost 5 en-l7a-ylpropiolate hydrochloride melting at 232236 with gas evolution. The product has the formula Example 5 GEC 0 O O CHgCHgCHgN(CH )g CH3 1 .HCl

Example 6 Z-pyrrolidinoethyl 313,175 dihydr0xyandrost-5-en-1 7ozylpropiolate hydrochloride-A mixture of 12 parts of 3;8,17,B dihydroxyandrost 5 en l7ot-ylpropiolic acid, 5 parts of N-(Z-chIoroethyl)pyrrolidine, and 500 parts of absolute 2-propanol is heated at the boiling point under reflux for 16 hours. The reaction mixture is then cooled to 0, whereupon the precipitate which forms is filtered off and taken up in a minimum amount of hot absolute etha- I101. To the hot ethanol solution is added sutficient anhydrous ether to bring about incipient precipitation. The precipitate thrown down on cooling is filtered off and recrystallized from a mixture of aqueous 80% ethanol and ether to give 2-pyrrolidinoethyl 35,175-dihydroxyandrost- 5-en-l7a-ylpropiolate hydrochloride. The product starts to melt and darkens at 253", with melting being completed at 280 or above, depending upon the rate of heating. The product has the formula QECOOOCHzCHr-N Example 7 CECCOOCHZOH2CH2N CH3 I OH Example 8 3 piperidinopropyl 175 hydroxy 3 oxoandrost 4 en 17a ylpropiolate hydrchloride.-A mixture of 30 parts of 17 -hydroXy-3-oxoandrost-4-en-17or-ylpropiolic acid, parts of N-(3-chloropropyl)piperidine, and 400 parts of absolute Z-butanol is heated at the boiling point under reflux for 16 hours. Solvent is thereupon removed by vacuum distillation and the residue taken up in absolute ethanol. Sufiicient anhydrous other is added to the ethanol solution to precipitate 3-piperidinopropyl 175 hydroxy 3 oxoandro'st 4 en 17a ylpropiolate hydrochloride, which is recowered on a filter and dried in air. The :product thus isolated has the formula CECC O O CH2CH2CH2-N 5 What is claimed is: 1. A compound of the formula 950 C O O-lower alkylene-Z --OH.

wherein X represents a member of the class consisting of 5-hydroxymethylene and carbonyl radicals, the lower alkylene radical called for separates the groups attached thereto by at least 2 carbon atoms, Z represents a member of the class consisting of di(lower alkyl) amino, pyrrolidino, and piperidino radicals, and the dotted line represents a 5(6) double bond when X represents a 5-hydroxymethylene radical and a 4(5) double bond when X represents a carbonyl radical.

2. A compound of the formula wherein the lower alkylene radical called for separates the groups attached thereto by at least 2 carbon atoms.

3. 2 dimet-hylarninoethyl 35,175 dihydroxyandrost- 5 en 17a ylpropiolate.

4. 2 dimethylaminoethyl 35,175 dihydroxyandrost- 5 en 17m ylpropiol ate.

5. 3 dimethylarnino propyl 35,175 dihydroxyandrost 5 en 17oz ylpropiolate.

6. A compound of the formula CEC C O O-lower alkylene-N (lower alkyl): CH

wherein the lower alkylene radical called for separates the groups attached thereto by at least 2 carbon atoms.

7. 2 diethylaminoethyl hydroxy 3 oxoandrost 4 en 17 a ylpropiolate. 8. A compound of the formula 0 EC 0 0 0 -lower alkylene-N No references cited.

LEWIS GOTTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N00 3,183,22 "Ma 11, 1965 Robert W Hamilton et a1 It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 6, line 58, for 2 'c1imethylaminoethyl read H Z-diethylaminoethyl H column 6, line 40, for "3 dimethy1-- amino propyl" read '5'd1methy1aminoprop'y1.

Signed and sealed this 28th day of June 19661 (SEAL) Attest:

ERNEST W. SWIDER Attesting Officer EDWARD J. BRENNER Commissioner of Patents 

1. A COMPOUND OF THE FORMULA 